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Salivary lesion (LEL) represents a unique disease, and some patients have malignant transformations. The study aims were to estimate the frequency of malignant transformation and the subtype of the malignant component and to identify factors associated with malignant transformation and subtype of the malignant component in patients with LEL.This study was based on a retrospective cohort study between 2005 and 2017 from patients who were diagnosed as LEL. The predictor variable was composed of a set of variables grouped into demographic, clinical, and pathologic features. The outcome variables were malignant transformation status and subtype of the malignant components. All parameters between the predictor variables and outcome variables were analyzed using the χThe sample was composed of 252 cases of LEL (including with or without malignant transformation) with a mean age of 50.3 years; 58 (58 of 252; 23.0%) were males, 194 (194 of 252; 77.0%) were females. The parotid gland was the most common site of LEL (206 of 252; 81.7%), and 36.5% (92 of 252) of the patients had a history of Sjögren syndrome (SS). Masses greater than 2 cm in diameter had evidence of malignant transformation (P .001). Factors associated with the subtype of malignant components were a history of SS (P .001) and Epstein-Barr virus infection. The percentages of nonmalignant transformations, LEL with extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT lymphoma), and LEL progressing to lymphoepithelial carcinoma were 44.8 (113 of 252), 47.6 (120 of 252), and 7.6% (19 of 252), respectively.More than half of cases have a malignant transformation, and MALT lymphoma is the most common malignant subtype. A larger mass (2 cm) is an independent indicator of malignant transformation in LEL patients. History of SS among LEL patients is considered a risk factor for MALT lymphoma.

GPR34 translocation and mutation are specifically associated with salivary gland MALT lymphoma (SG-MALT-lymphoma). The majority of GPR34 mutations are clustered in its C-terminus, resulting in truncated proteins lacking the phosphorylation motif important for receptor desensitization. It is unclear why GPR34 genetic changes associate with SG-MALT-lymphoma and how these mutations contribute to the development of lymphoma. We generated isogenic Flp-InTRex293 cell lines that stably expressed a single copy of GPR34 or its various mutants and performed a range of in vitro assays. We found that the GPR34 Q340X truncation, but not the R84H and D151A mutants, conferred a significantly increased resistance to apoptosis and greater transforming potential than the GPR34 wild type. The GPR34 truncation mutant had a significantly delayed internalization compared with the wild type after ligand (lysophosphatidylserine) stimulation. Among the 9 signaling pathways examined, the GPR34 Q340X truncation, and to a lesser extent the D151A mutant, significantly activated CRE, NF-κB, and AP1 reporter activities, particularly in the presence of ligand stimulation. We further described the enhanced activities of phospholipase-A1/2 in the culture supernatant of Flp-InTRex293 cells that expressed the GPR34 Q340X mutant, as well as their potential to catalyze the synthesis of lysophosphatidylserine from phosphatidylserine. Importantly, phospholipase-A1 was abundantly expressed in the duct epithelium of salivary glands and those involved in lymphoepithelial lesions (LELs). Our findings advocate a model of paracrine stimulation of malignant B cells via GPR34, in which phospholipase A is released by LELs and hydrolyzes the phosphatidylserine exposed on apoptotic cells, generating lysophosphatidylserine, the ligand for GPR34. Thus, GPR34 activation potentially bridges LELs to genesis of SG-MALT-lymphoma.

Sjögren’s Syndrome (SS) is a chronic autoimmune disorder characterized by focal mononuclear cell infiltrates that surround the ducts of the exocrine glands, impairing the function of their secretory units. Compared to other autoimmune disorders, SS is associated with a notably high incidence of non-Hodgkin lymphoma (NHL) and more frequently mucosa associated lymphoid tissue (MALT) lymphoma, leading to increased morbidity and mortality rates. High risk features of lymphoma development include systemic extraepithelial manifestations, low serum levels of complement component C4 and mixed type II cryoglobulinemia. The discrimination between reactive and neoplastic lymphoepithelial lesion (LEL) is challenging, probably reflecting a continuum in the evolution from purely inflammatory lymphoid infiltration to the clonal neoplastic evolution. Early lesions display a predominance of activated T cells, while B cells prevail in severe histologic lesions. This strong B cell infiltration is not only a morphologic phenomenon, but it is also progressively associated with the presence of ectopic germinal centers (GCs). Ectopic formation of GCs in SS represents a complex process regulated by an array of cytokines, adhesion molecules and chemokines. Chronic antigenic stimulation is the major driver of specific B cell proliferation and increases the frequency of their transformation in the ectopic GCs and marginal zone (MZ) equivalents. B cells expressing cell surface rheumatoid factor (RF) are frequently detected in the salivary glands, suggesting that clonal expansion might arise from antigen selection of RF-expressing B cells. Abnormal stimulation and incomplete control mechanisms within ectopic lymphoid structures predispose RF MZ like cells to lymphoma development. Immunoglobulin recombination, somatic mutation and isotype switching during B cell development are events that may increase the translocation of oncogenes to immunoglobulin loci or tumor suppressor gene inactivation, leading to monoclonal B cell proliferation and lymphoma development. Concerning chronic antigenic stimulation, conclusive data is so far lacking. However immune complexes containing DNA or RNA are the most likely candidates. Whether additional molecular oncogenic events contribute to the malignant overgrowth remains to be proved.

Duodenal mucosa-associated lymphoid tissue (MALT) lymphoma is an extremely rare tumor. Herein, we report multidisciplinary treatment of a patient with synchronous development of primary MALT lymphoma of the duodenum and gastric cancer. A 70-year-old woman was referred to our hospital for examination of a gastric cancer initially diagnosed by a local medical doctor. Esophagogastroduodenoscopy showed an elevated lesion with a central ulcer in the lower body of the stomach, and a partially whitish aggregated lesion in the descending portion of the duodenum. Histopathological examination of biopsy specimens from the gastric lesion showed moderately differentiated adenocarcinoma, and duodenal specimens showed low-grade MALT lymphoma composed of atypical lymphoid cells with a lymphoepithelial lesion. The patient underwent distal gastrectomy with regional lymph node dissection for the gastric cancer. Histological examination showed muscularis propria invading adenocarcinoma with two lymph node metastases. After operation, four courses of systemic rituximab treatment were administered for the MALT lymphoma, followed by adjuvant S-1 (tegafur/gimeracil/oteracil) chemotherapy for the gastric cancer. In the 4 months after operation, the patient was well with no evidence of recurrence. To the best of our knowledge, this is the second reported case of synchronous gastric adenocarcinoma and duodenal MALT lymphoma in the English literature.

Objectives The aim of this study was to evaluate the diagnostic value of immunoglobulin (Ig) clonal gene rearrangements for mucosa-associated lymphoid tissue (MALT) lymphoma of the parotid gland. Study Design We collected and retrospectively analyzed clinical data of 21 patients referred to our institution between 2009 and 2017. Eight patients had been primarily diagnosed MALT lymphoma of the parotid gland and the remaining patients with lymphoepithelial lesion. Paraffin-embedded tissues were chosen for extracting genomic DNA and multiplex primer polymerase chain reaction amplification by using BIOMED-2 primers. Polymerase chain reaction amplification products were analyzed by heteroduplex analysis. Results Generally, 17 patients were identified to have parotid gland MALT lymphoma; 47.06% of them had Sjogren syndrome. The sensitivity of IGH VH-JH FR1, FR2, FR3, IGK Vκ-Jκ, and IGK (Vκ-Kde and intron-Kde) as targets was 76.47%, 82.35%, 88.24%, 29.41%, and 35.29%, respectively. The sensitivity of combined application of the above-mentioned 3 IGH primers as targets was 100%. The sensitivity of combined application of the above two IGK primers as targets was 58.82%. Conclusions Ig clonal gene rearrangements assays using BIOMED-2 protocol can be a highly reliable diagnostic method for parotid gland MALT lymphoma. For patients with Sjogren syndrome along with histologically benign lymphoepithelial lesion, identification of Ig clonal gene rearrangements is important for routine differential diagnosis.

Introduction Although eosinophils are commonly present on the mucosa of the gastrointestinal tract, various pathological conditions may cause a secondary increase in eosinophil quantity. Presentation of case A 78-year-old man was referred to our hospital due to abdominal pain. Examinations revealed an ulcerative lesion with white moss in the terminal ileum and severe stenosis on the oral and anal sides. Tissue biopsies obtained from the ulcer margins showed a predominance of chronic inflammatory cells and abundant eosinophils in addition to lymphocytes/plasma cells. Secondary causes of tissue eosinophilia were suspected; however, the diagnosis could not be confirmed because of atypical endoscopic findings. Partial resection of the ileum was performed for therapeutic and diagnostic purposes. Histopathology of the resected specimen identified a lymphoepithelial lesion with an invasive tendency. While CD20 staining was positive, MUM-1 and Bcl-6 staining were negative. Based on these findings, the lesion was diagnosed as a small intestinal mucosa-associated lymphoid tissue lymphoma (Lugano staging, stage II1). Discussion Hypereosinophilia in this lesion was suggested to be secondary to chronic inflammation due to tumor growth or impaired transit. Conclusion There is a type of gastrointestinal MALT lymphoma showing an invasive tendency. In such cases, it may demonstrate atypical findings and hypereosinophilia in gastrointestinal tissues., Highlights • Eosinophils are commonly present on the GI mucosa floor. • Abnormal/pathological conditions, include malignant lymphoma, can increase this concentration. • Some gastrointestinal MALT lymphomas have a strong invasive tendency. • Lymphocytes may infiltrate the deep ulcer and form severe stenosis. • Sometimes, it is difficult to identify by endoscopic findings and needs surgical specimen for definitive diagnosis.

A 39-year-old female patient with fibromyalgia and complaints of xerostomia was referred to a dental surgeon because of the suggestion of Sjogren Syndrome (SS). She had major salivary gland scintigraphy suggestive of parotid gland obstruction. She also had a positive serologic test for anti-Ro but negative tear break-up and Schirmer tests. Minor salivary gland biopsy was performed, with 7 glands collected. Histologic examination showed the presence of 5 lymphocytic foci (each with ≥ 50 lymphocytes) around ducts (some dilated) or blood vessels, adjacent to normal appearing acini. Fibrosis, adipose infiltration, germinal center, and lymphoepithelial lesion were not observed. The whole gland tissue measurement was 21 mm², resulting in a focal score of 1 (1 focus/4 mm2), which is considered a focal lymphocytic sialadenitis histologically compatible with SS. The final diagnosis of SS was established based on the combination of histology, clinical, and serology results. The patient is under treatment with a rheumatologist.

Helicobacter infection is considered the major predisposing factor for gastric mucosa-associated lymphoid tissue (MALT) lymphoma with initial infection likely occurring in childhood. Primary gastric MALT lymphoma most commonly occurs in patients older than 50 years which is attributed to the lengthy chronic infection time required before the development of MALT lymphoma. Our study analyzes the histologic features and presence of immunoglobulin heavy chain (IGH) clonality in Helicobacter-associated chronic gastritis (62 cases) and Helicobacter-negative chronic gastritis (17 cases) biopsies within the pediatric population, diagnosed between 1996 and 2018. Helicobacter-associated gastritis was more likely to show active inflammation (P=0.01), with no significant difference in number of germinal centers or the strength, linear property, or depth of the inflammatory infiltrate. In total, 47% (29/62) of the Helicobacter-associated cases had at least 1 lymphoepithelial lesion, equivocal or definitive (a modified Wotherspoon score of 3 to 5), compared with 24% (4/17) of the Helicobacter-negative cases (P=0.5). All cases with lymphoepithelial lesions were assessed for IGH clonality, showing the presence of monoclonality in 27% (8/30) of evaluable cases. None of our patients were diagnosed with gastric lymphoma within available follow-up data. Although 4% of our cases could be considered MALT lymphoma in an adult patient based on prominent lymphoepithelial lesions and IGH monoclonality, caution is advised when diagnosing lymphoma in the pediatric population given the good prognosis of Helicobacter-associated gastritis in this age group. It is unclear if these monoclonal lymphoid proliferations require close follow-up.

Follicular lymphoma (FL) shows co-expression of B-cell lymphoma 2 (BCL2) and CD10, whereas downexpression of CD10 is occasionally experienced in gastrointestinal (GI) FL with unknown significance. Gastrointestinal FL is a rare variant of FL, and its similarity with mucosa-associated lymphoid tissue lymphoma was reported. We investigated the clinicopathological and genetic features of CD10 downexpressed (CD10down ) GI-FL. The diagnosis of CD10down FL was carried out with a combination of pathological and molecular analyses. The incidence of CD10down GI-FL was shown in 35/172 (20.3%) cases, which was more frequent than nodal FL (3.5%, P < 0.001). The difference was additionally significant between GI-FL and nodal FL when the analysis was confined to primary GI-FL (55.2% vs 3.5%, P < 0.001). Compared to CD10+ GI-FL, CD10down GI-FL significantly involved the stomach or large intestine (P = 0.015), and additionally showed the downexpression of BCL6 (P < 0.001). The follicular dendritic cell meshwork often showed a duodenal pattern in the CD10down group (P = 0.12). Furthermore, a lymphoepithelial lesion was observed in 5/12 (40%) gastric FL cases, which indicated caution in the differentiation of mucosa-associated lymphoid tissue lymphoma. Molecular analyses were undertaken in seven cases of CD10down GI-FL, and an identical clone was found between CD10down follicles and CD10+ BCL2+ neoplastic follicles. In the diagnosis of cases with CD10down BCL2+ follicles, careful examination with molecular studies should be carried out.

Differentiating low-grade lymphoma from preexisting sarcoidosis is difficult because of their pathological similarity. This article describes a case of pulmonary mucosa-associated lymphoid tissue lymphoma associated with pulmonary sarcoidosis. The patient, a 45-year-old Japanese man, presented with a 10-year history of pulmonary sarcoidosis and 5-year history of ocular sarcoidosis with histologic findings. Because only the right S3 lung nodule had gradually enlarged, partial resection was performed. Pathological study revealed noncaseous epithelioid granulomas with lymphoplasmacytic proliferation but also marked lymphoid cell proliferation with lymphoepithelial lesion findings that differed from findings of typical sarcoid lesions. Our lymphoepithelial lesion evaluation via immunohistochemistry and analysis of Ig heavy-chain gene rearrangements with assessment of Propionibacterium acnes-specific antibody reactions allow us to report, for the first time, this case of pulmonary mucosa-associated lymphoid tissue lymphoma associated with pulmonary sarcoidosis in exactly the same location, which may be significant for differentiating these diseases and understanding their pathogenic association.

The present case report presents a rare case of Epstein-Barr virus (EBV)-associated early gastric carcinoma with lymphoid stroma, accompanied by lymph node metastasis. A 61-year-old woman was referred to our hospital following observation of a gastric mass lesion that was initially diagnosed at a medical check-up. Esophagogastroduodenoscopy revealed a slightly elevated lesion with a central irregular depression in the middle third of the stomach. Endoscopic ultrasonography revealed a well-circumscribed hypoechoic mass located predominantly within the submucosa and the mucosa. Biopsy specimens of the lesion indicated the possibility of carcinoma with lymphoid stroma with a lymphoepithelial lesion. Abdominal contrast-enhanced computed tomography (CT) revealed a well-defined mass with homogeneous enhancement approximately 1.2 cm in diameter in the middle part of the stomach, demonstrating lymphadenopathy in the perigastric area at a maximum size of 1.4 cm in diameter. The patient underwent laparoscopic distal gastrectomy with regional lymphadenectomy due to suspicion of a gastric carcinoma with lymphoid stroma. Histopathological and immunohistochemical findings verified the diagnosis of carcinoma with lymphoid stroma, which were positive for EBV-encoded RNA (EBER-ISH) by in situ hybridization. There was one lymph node metastasis, which was in line with the CT imaging. Marked infiltration of lymphoid cells was observed in the tumor stroma, which were negative for EBER-ISH. The present case is informative of the pathological characteristics of this condition, and clinicians should recognize the features of this disease to make an accurate diagnosis and select the appropriate treatment.

Nonsebaceous lymphadenoma is an uncommon salivary gland tumor. It consists of lymphoid and epithelial components that lack sebaceous differentiation. Herein, we present a 44-year-old woman with left a submandibular gland tumor. The tumor is well-circumscribed and solid without ductal or cystic formation. The epithelial cells intermingle with lymphoplasma cells. The epithelial cells show moderate cytologic atypia and a few mitoses with no viral infection. Histologically, the tumor had features of nonsebaceous lymphadenoma with unusual findings of nuclear atypia and marked lymphoepithelial differentiation. Atypical nonsebaceous lymphadenoma with diffuse lymphoepithelial differentiation is rare and important to recognize to avoid misdiagnosis.

There is increasing evidence concerning the occurrence of malignant lymphoma among people suffering from Mikulicz disease, also termed benign lymphoepithelial lesion (BLEL) and immunoglobulin G4‑associated disease. However, the underlying molecular mechanism of the malignant transformation remains unclear. The present study aimed to investigate the gene expression profile between BLEL and malignant lymphoepithelial lesion (MLEL) conditions using tissue microarray analysis, to identify genes and pathways which may be associated with the risk of malignant transformation. Comparing gene expression profiles between BLEL tissues (n=13) and MLEL (n=14), a total of 1,002 differentially expressed genes (DEGs) were identified including 364 downregulated and 638 upregulated DEGs in BLEL. The downregulated DEGs in BLEL were frequently associated with immune‑based functions, immune cell differentiation, proliferation and survival, and metabolic functions, whereas the upregulated DEGs were primarily associated with organ, gland and tissue developmental processes. The B cell receptor signaling pathway, the transcription factor p65 signaling pathway, low affinity immunoglobulin γ Fc region receptor II‑mediated phagocytosis, the high affinity immunoglobulin ε receptor subunit γ signaling pathway and Epstein‑Barr virus infection, and pathways in cancer, were the pathways associated with the downregulated DEGs. The upregulated DEGs were associated with three pathways, including glutathione metabolism, salivary secretion and mineral absorption pathways. These results suggested that the identified signaling pathways and their associated genes may be crucial for understanding the molecular mechanisms underlying malignant transformation from BLEL, and they may be considered to be markers for predicting malignancy among the BLEL group.

Lymphocyte-only aspirates pose a significant diagnostic challenge in the interpretation of thyroid fine-needle aspiration specimens. Differential diagnosis includes Hashimoto thyroiditis, lymphoma, intrathyroidal lymph node, intrathyroidal thymoma, and thyroglossal duct cyst. Hashimoto thyroiditis especially in the florid lymphoid phase usually presents as lymphocyte-only aspirates. During this phase, numerous hyperplastic lymphoid follicles are seen throughout the gland, and they often replace the thyroid parenchyma. Lymphomas of the thyroid typically occur in older patients, almost always arise in a background of Hashimoto thyroiditis and are of B-cell lineage. Primary lymphomas of the thyroid gland are mainly diffuse large B-cell lymphoma (DLBCL) and extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) and to a much lesser extent Hodgkin and small lymphocytic lymphoma. Given the limitations of establishing a lymphoma diagnosis with only cytomorphology, morphological evaluation is commonly augmented with flow cytometry or immunohistochemistry in the diagnostic workup of lymphocyte-only fine-needle aspirates from the thyroid.

Tongue is formed of a mass of muscles and salivary gland embedded in anterior highly vascular and posterior lymphoid stroma and covered by specialized surface epithelium. Growths from all of these heterogonous components may occur resulting in a wide variation in clinical features and behavior, ranging from self-limiting to aggressive lesions. Therefore, surgical excision is the treatment of choice. The aim of the current study is to report three different lesions that came to the Oral Surgery Department in the Faculty of Oral and Dental Medicine, Cairo University. Following clinical and histopathological examination, the diagnosis of reactive lymphoproliferative lesion, cystic lymphoepithelial lesion, and developmental lymphatic vessel malformation was reached.

The risk of misdiagnosing neoplastic cells typically infiltrating an epithelium forming a lymphoepithelial lesion as poorly differentiated gastric cancer in endoscopic biopsies, particularly in low-grade mucosa-associated lymphoid tissue (MALT) lymphomas, is described. A 76-year-old woman was referred for management of a poorly differentiated gastric adenocarcinoma. Diagnostic endoscopy in our unit showed a 2 cm raised, submucosal lesion with central erosion in the upper body of the stomach, but repeat biopsies of the lesion were interpreted as inflamed gastric mucosa and negative for malignancy. Systematic gastric biopsies to rule out any foci of MALT lymphoma changes were also negative. Therefore, endoscopic submucosal dissection was performed to obtain an accurate specimen. Histology revealed centrocyte-like cells and a lymphoepithelial lesion invading into the mucosa with obliteration of the gastric glands, which was initially interpreted as poorly differentiated adenocarcinoma.

This report describes a 60-year-old man with concurrent gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) and classical Hodgkin lymphoma (CHL). Atypical, medium-sized, lymphoid cells proliferated in the mucosa to muscular layer of the stomach showing a lymphoepithelial lesion; admixed with Hodgkin/Reed-Sternberg (HRS) cells and an inflammatory cell background. MALT lymphoma cells expressed CD20, CD79a, PAX5, and BOB.1, and HRS cells expressed CD30, CD15, Epstein–Barr virus–encoded RNA, and EBV-latent membrane protein 1. Only CHL invaded into the regional lymph nodes. Two possibilities of transformation of MALT lymphoma into CHL and de novo CHL within MALT lymphoma are discussed.

Mucosa-associated lymphoid tissue (MALT) lymphoma of the ocular adnexae is rare. A 39-year-old woman presenting with proptosis was diagnosed to have non-Hodgkin’s lymphoma with intermediate-sized cells and lymphoepithelial lesion. Unlike most MALT lymphomas, this lymphoma was found to be CD5-positive. Small lymphocytic lymphoma/chronic lymphocytic leukemia and lymphoplasmacytic lymphoma are two other entities that are CD5-positive and have a morphological pattern similar to MALT lymphoma. The case report and approach to the diagnosis is discussed.

Anhand der europaisch-amerikanischen Klassifikationskriterien lasst sich die Diagnose einer Autoimmunsialadenitis bei Sjogren-Syndrom in den meisten Fallen einfach stellen oder ausschliesen. Zusatzlich ist die Sonographie in der Hand des HNO-Arztes hilfreich in der Diagnosestellung und Nachbeobachtung zur Fruherkennung eines MALT-Lymphoms, das 5–10% der Patienten entwickeln. Die Therapie der Sicca-Symptomatik erfolgt symptomatisch durch Substitution von Flussigkeit und Stimulation mit oralen Cholinergika. Kortikosteroide oder Antibiotika konnen bei schweren entzundlichen Schuben der Autoimmunsialadenitis hilfreich sein. Eine systemische Therapie mit immunmodulatorischen Medikamenten wie Azathioprin oder Cyclophosphamid ist Patienten mit extraglandularer Manifestation vorbehalten, doch ist deren Wirksamkeit nicht durch Studien belegt. Mit Rituximab, einem monoklonalen CD20-Antikorper, besteht anscheinend nun erstmals die Moglichkeit einer kausalen Therapie; hierunter bilden sich die erkrankungstypischen lymphoepithelialen Lasionen in den Speicheldrusen zuruck und die Speichelproduktion bessert sich. Doch sind grosere Therapiestudien notig, um diese neue Behandlungsmoglichkeit endgultig bewerten zu konnen. Eine optimale Betreuung der Patienten setzt eine interdisziplinare Zusammenarbeit vom HNO-Arzt, Kieferchirurg, Rheumatologen, Augenarzt, Zahnarzt und Pathologen voraus.